Some physiologically active substances cannot be (sufficiently) filter-sterilized due to their low water solubility in an attempt to administer them to organisms as drugs. Also, some physiologically active substances are difficult to dissolve in an aqueous solution or an emulsion prepared from the aqueous solution for administration to organisms.
Various methods have been attempted to improve the water solubility of drugs such as physiologically active substances. For example, a carrier-drug conjugate (so-called a drug derivative) is known in which a highly water-soluble carrier is covalently bonded to a drug. A hydrophilic amino acid sequence, polyethylene glycol (PEG), or the like is known as the carrier.
Such a drug derivative, however, differs in steric structure from the original drug and therefore exhibits different pharmacokinetic, immunogenic, toxicological, or pharmacological properties, etc., compared with the original drug. When the drug derivative is used as, for example, a vaccine, its antigenicity is known to be generally lower than that of the unmodified drug.
A drug with PEG added as a carrier (PEGylated drug) is resistant to biodegradation. Thus, the PEGylated drug, when continuously administered into an organism, might accumulate in the organism to cause chemical injury to the organism (Patent Literature 1). Furthermore, PEG has a molecular weight distribution (polydisperse nature). Thus, the PEGylation of drugs forms many monomeric isoforms having distinctive activity (different monomeric isoforms: structurally different proteins), because of the difference in the binding site or molecular weight of added PEG. These formed isoforms might compete with each other for binding to a drug acceptor molecule (Non Patent Literature 1).
A carrier-linker-drug conjugate has also been developed in which a drug and a carrier are bonded via a linker moiety. This conjugate is designed such that the bond between the carrier-linker moiety and the drug is cleaved at a target site (in blood, etc.) to release the drug itself. For such cleavage of the bond, light or enzymatic cleavage has been used as a trigger. Unfortunately, the in vivo light irradiation of the target site is difficult, and the light might damage the organism. Also, in the case of the enzymatic cleavage, the amount of an enzyme is known to largely differ among individuals or depending on administration sites. Thus, the problem of this approach is to cause variations in the effect of the drug therapy.
In this respect, the utilization of autohydrolysis based on intramolecular catalysis in the linker has been attempted for the cleavage of the carrier-linker moiety from the drug in the carrier-linker-drug conjugate. A conjugate in which a linker moiety is bonded through an amide bond to a drug via an amino group derived from the drug has been reported as this type of conjugate (Patent Literature 2). The cleavage mechanism of this conjugate is based on the cleavage of the amide bond by cyclization-activation resulting from cyclic imide formation in the linker.